Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation
Expression of DLK1 in hematopoietic cells results in inhibition of differentiation and proliferation
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DOI：
10.1038/sj.onc.1208637
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发表时间：
2005-06-01
期刊：
影响因子：
8
通讯作者：
Bhatia, R
中科院分区：
文献类型：
--
作者：
Li, L;Forman, SJ;Bhatia, R
Delta样（DLK 1）基因在骨髓增生异常综合征（MDS）患者的CD 34+细胞中过表达。DLK 1编码与notch/delta/serrate家族同源的EGF样同源异型跨膜蛋白。尽管外源性DLK 1促进了小鼠造血干细胞的维持，但DLK 1在造血细胞中过表达的功能效应尚不清楚。我们发现，异位表达DLK 1显着抑制人早幼粒细胞HL-60细胞的分化和增殖。与前脂肪细胞不同，其中膜结合蛋白的蛋白水解加工和可溶形式的释放介导分化抑制，细胞外结构域的蛋白水解释放不是抑制造血细胞分化所必需的。然而，胞内结构域相互作用对DLK 1的功能至关重要。我们的结论是DLK 1在造血细胞中的过度表达具有重要的功能后果。我们的研究确定了新的分子机制，并表明DLK 1作为可溶性和跨膜表达蛋白具有活性。我们的研究结果支持DLK 1在MDS异常造血中的作用的进一步调查。
The Delta-like (DLK1) gene is overexpressed in CD34+ cells from myelodysplastic syndrome (MDS) patients. DLK1 encodes an EGF-like homeotic transmembrane protein homologous to the notch/delta/serrate family. Although exogenous DLK1 promotes maintenance of murine hematopoietic stem cells, the functional effects of DLK1 overexpression in hematopoietic cells are unknown. We show that ectopically expressed DLK1 significantly inhibits differentiation and proliferation of human promyelocytic HL-60 cells. Unlike preadipocytes, where proteolytic processing of membrane-bound protein and release of a soluble form mediates differentiation inhibition, proteolytic release of the extracellular domain was not required for inhibition of hematopoietic cell differentiation. However, intracellular domain interactions were critical to this DLK1 function. We conclude that DLK1 overexpression in hematopoietic cells has important functional consequences. Our studies identify novel molecular mechanisms and indicate that DLK1 has activity both as a soluble and a transmembrane expressed protein. Our results support further investigation of the role of DLK1 in abnormal hematopoiesis in MDS.